A central problem in biology is to understand how cells traffic through the body. Which cells have been recruited to a tissue, and which arose from proliferation or differentiation of tissue-resident cells? How are cells retained in a tissue, and what signals them to move on? What is the path of migration? Many of these questions, in areas ranging from developmental biology to immunology to tumor metastasis to regenerative medicine, remain unanswered because we do not have tools that provide spatial control over gene expression. To address this problem, we propose to generate and characterize a mouse expressing a photoactivatable Cre recombinase (PA-Cre), which will allow us to genetically manipulate cells in a specific place at a specific time using a defined light frequency. This tool will enable us to permanently label cells of interest and manipulate conditional alleles in cell populations defined not only by their surface phenotypes and stage of development but also by their physical location. As a proof-of-principle, we will use this mouse to identify the cell-of-orgin in a novel mouse model of cutaneous T cell lymphoma.